Drugs for treating respiratory and nasal disorders are frequently administered in aerosol formulations through the mouth or nose. See generally P. Byron, Respiratory Drug Delivery, CRC Press, Boca Raton, Fla. (1990). One widely used method for dispensing such an aerosol drug formulation involves making a suspension formulation of the drug as a finely divided powder in a liquefied gas known as a propellant. The suspension is stored in a sealed container capable of withstanding the pressure required to maintain the propellant as a liquid. The suspension is dispensed by activation of a dose metering valve affixed to the container.
A metering valve may be designed to consistently release a fixed, predetermined amount of the drug formulation upon each activation. As the suspension is forced from the container through the dose metering valve by the high vapor pressure of the propellant, the propellant rapidly vaporizes, leaving a cloud of very fine particles of the drug formulation. This cloud is usually directed into the body of the patient by a channeling device, e.g., a cylinder-like or cone-like passage, with one of its ends attached to the outlet of the pressurized container, and the other end inserted in the mouth or nose of the patient. Concurrently with the activation of the aerosol dose metering valve, the patient inhales the drug formulation particles into the lungs or nasal cavity. Systems for dispensing drugs in this way are known as "metered dose inhalers (MDI's)." See Byron, supra at 167-207.
Many materials, including drug formulations, have a tendency to aggregate (also referred to as "flocculate" or "clump-up") when stored as fine particles having dimensions of a few microns in a suspension. For an aerosol delivery system to work properly the particle size should generally not exceed about five microns. As the particle size exceeds five microns, it becomes increasing difficult to maintain an efficacious aerosol dose with a predicable dispersion pattern upon activation of the metering valve. Further, the suspension should be uniform, that is, substantially free from large aggregates of the drug particle and be substantially homogenous throughout the container.
To minimize or prevent the problem of aggregation of fine particles, compounds known as surface active agents, or surfactants, are often used to coat the surfaces of the fine particles and assist in wetting the particles with an aerosol propellant. The use of surfactants in this way to maintain substantially uniform suspensions is said to "stabilize" the suspensions.
For several years the chlorofluorocarbons (CFC's) have gained widespread acceptance as the propellants of choice for inhalation drug formulations. However, in the past few years CFC's have been shown to cause depletion of the ozone layer of the atmosphere: a serious environmental problem. Scientists and governmental officials around the world have called for a phase-out of the use of CFC's, and some countries, e.g., Sweden, have banned their use entirely.
In recent years hydrofluorocarbon (HFC) propellants such as 1,1,1,2-tetrafluoroethane (also known as "propellant 134a") and heptafluoropropane (also known as "propellant 227") have been promoted as an environmentally acceptable alternative to CFC propellants. While attractive in many respects, in the area of aerosol pharmaceuticals it has proven particularly difficult to form stablized compositions with such propellants. In light of the need to reduce the use of CFC propellants, there is a continuing need for the development of stabilized aerosol formulations containing HFC propellants.